The present invention is directed to a process for purifying a solvent suitable for use with a pharmaceutical agent and to the purified solvent and pharmaceutical compositions prepared therewith.
Administration of pharmaceutical compounds, and in particular administration by injection, requires a solvent or carrier that is suitable for administration to the patient. The solvent used in conjunction with the pharmaceutical agent must, when combined with the pharmaceutical agent, produce an effective composition for injection, ideally having good shelf life. The solvent should be non-toxic to the patient and compatible with the particular pharmaceutical agent to be injected. Many solvents are not especially efficient for solubilizing the pharmaceutical agent to enable an effective composition for administration, while simultaneously possessing these advantageous qualities.
Compositions containing polyethoxylated castor oil and similar solvents are frequently used in combination with a pharmaceutical agent to produce a mixture suitable for administration by injection. The solvents acceptable for pharmaceutical use are set forth in a United States Pharmacopoeia (USP) with the acceptable limits for various parameters of these solvents in a National Formulary (NF). A potential problem associated with such solvents is that acids, salts or other ionic impurities, as well as residual water in the solvent or solvent system, even if within the acceptable limits, can catalyze the degradation of the pharmaceutical agent. For example, it is believed that carboxylate anions present in polyethoxylated castor oil can catalyze the decomposition of paciltaxel, even at levels within the defined limits set forth in the National Formulary. See, for example, U.S. Pat. No. 5,504,102, incorporated herein by reference. The U.S. Pat. No. 5,504,201 patent discloses removing the carboxylate anions from polyethoxylated castor oils by acid addition or alumina adsorption. A solvent with sufficiently low levels of particular deleterious impurities will yield a more stable pharmaceutical agent containing compositions.
Because such solvents and solvent systems are combined with pharmaceuticals used in the treatment of, among other things, cancer, the importance of developing a method for removing impurities that deleteriously effect the stability of the pharmaceutical agent is apparent. There is a need for the development of a solvent or cosolvent system that does not negatively impact the potency or purity of the pharmaceutical agent and which provides for good shelf life. The present invention addresses the problems of loss of effectiveness of the pharmaceutical agent due to decomposition during storage. Moreover, the present invention does not affect the pH during purification of the solvent
The present invention provides a process for purifying a solvent for use in the formulation of a pharmaceutical agent composition. The invention also provides purified solvent produced by this process and a pharmaceutical composition comprising the purified solvent and a pharmaceutical agent, which composition has extended shelf-life. More particularly, the present invention is directed to an improved process for purifying a solvent which results in advantageously low quantities of salts, acids and various other ionic impurities, as well as low residual water content and enhanced clarity. In a preferred aspect of the invention, the process involves the purification of polyethoxylated castor oils, sometimes called polyoxyethylated castor oils, by forming a solution of the solvent in alcohol and contacting the solution with an activated carbon column, followed by contacting the solution with an ion exchange resin column and then evaporating the residual water and alcohol. The resin column follows the charcoal column in the preferred embodiment so that, in the event any charcoal particulates remain after the charcoal column, they will be eliminated by the resin column. While not wanting to be bound by theory, it is believed that contact with the activated carbon removes water and unsaturated aliphatic and aromatic compounds by an adsorption mechanism. The ion exchange resin is believed to exchange cations and anions from the solvent with OHxe2x88x92 and H+.
The solvents that are purified are non-ionic surfactants. The solvent is preferably a condensation product of an alkylene oxide and an oil or fatty acid. The preferred solvent is a polyethoxylated castor oil, such as polyoxyl 35 castor oil, Cremophor RH60, or a similar solvent such as polysorbate 80. Still more preferably, the solvent is a polyoxyl 35 castor oil. Commercially available polyethoxylated castor oils to which the present process is particularly suited are sold under the trade name Cremophor, such as Cremophor EL and Cremophor RH60. In the present invention, the polyethoxylated castor oils such as Cremophor EL and Cremophor RH60 are treated to enhance clarity and reduce potassium, salt, acid, water content and other deleterious impurities.
It is another aspect of the present invention to provide purified polyethoxylated castor oils that, when employed to solubilize pharmaceutical agents, produce a pharmaceutical composition having an advantageously long shelf life.
In one embodiment, such as for purifying polyoxyl 35, the resulting, purified polyethoxylated castor oil has a specific gravity between 1.05 and 1.06 g/ml, a viscosity between 650 and 850 cps at 25xc2x0 C. an acid value (NF) of not more than 2.0, a hydroxyl value (NF) between 65 and 80, a potassium content less than or-equal to 15 ppm, a water percentage less than about 3.0%, and preferably less than or equal to 0.5%, a saponification of between 60 and 75 and an iodine value (NF) of 25 to 35.
In another embodiment, such as for purifying polysorbate 80, the resulting, purified solvent has a specific gravity between 1.06 and 1.09 g/ml, a viscosity between 300 and 500 cps., an acid value (NF) of not more than 2.2, a hydroxyl value (NF) between 65 and 80, a water percentage less than about 3.0%, and preferably less than or equal to 0.5%, and a saponification of between 45 and 55. Polysorbate 80 is a non-ionic surfactant and can be generally classified as a polyol with a similar chemical structure to the polyethoxylated castor oils and is hereinafter generally referred to as a polyethoxylated castor oil.
In another embodiment, such as for purifying Cremophor RH60, the resulting, purified polyethoxylated castor oil has a specific gravity of about 1.1 g/ml, a viscosity of about 211 cps. at 60xc2x0 C., an acid value (NF) less than 0.2, a hydroxyl value (NF) of about 69, an iodine value less than about 2, a water percentage of about 0.4%, a potassium value less than about 7 ppm, and a saponification of about 44.
The invention is also directed towards stabilized pharmaceutical compositions prepared from the solvent according to the invention. Preferred pharmaceutical compounds that may be combined with the solvent after purification include antineoplastic compounds such as teniposide, paclitaxel and camptothecin, immunosuppressive agents such as cyclosporin and tacrolimus, oil soluble vitamins, mixtures thereof and the like. A purified polyethoxylated castor oil having the preferred characteristics will produce a pharmaceutical composition having a good shelf life. In the preferred embodiment, the pharmaceutical agent is paclitaxel and the process is carried out so as to produce a polyethoxylated castor oil that, when combined with the paclitaxel in a pharmaceutical composition, will provide at least about 90% of the initial amount of paclitaxel after being stored at 40xc2x0 C. for ninety days. Still more preferably, the composition will provide at least about 97%xc2x15% paclitaxel after being stored at 40xc2x0 C. for ninety days.
To obtain this product, the process employs respective amounts of activated carbon and ion exchange resin, and passes the polyethoxylated castor oil through the respective columns at rates suitable to produce a purified polyethoxylated castor oil having the desired properties. One of ordinary skill in the art will be able to empirically determine appropriate amounts of activated carbon and ion exchange resin, and suitable flow rates to obtain the desired product in view of the present disclosure. It will be apparent, for example, that a minimal amount of resin or carbon will be necessary to obtain the desired result and that an excess amount or volume may result in residence times on the column that are too long. Similarly, after a sufficiently long period of use, it is believed that the resin and/or charcoal will become spent, and no longer function to remove the necessary impurities efficiently. These limitations can obviously be empirically determined by those of ordinary skill in the art by assaying the product and determining whether it falls within the desired specifications.
Preferably, the invention employs activated charcoal in the carbon column at a ratio of 0.19 to 0.2 Kg of charcoal per Kg of polyethoxylated castor oil, and an ion exchange resin at a ratio of 0.21 to 0.22 Kg of resin per Kg of polyethoxylated castor oil. More preferably, the ion exchange resin is a mixed bed ion exchange resin for exchanging H+ and OHxe2x88x92 for anions and cations present in the untreated solvent. At these ratios, the polyethoxylated castor oil is preferably passed through the carbon column at a rate of from about 0.16 to 0.22 column volumes per hour (cv/hr), and through the resin column at a rate that is no greater than about 0.30 cv/hr, and preferably between about 0.12 to about 0.30 cv/hr.
While not being bound by theory, it is believed that the critical parameter necessary to obtain the purified polyethoxylated castor oil having the desired characteristics is the time the unpurified oil spends on the respective columns. If the residence time is too short, then the columns will not remove sufficient amounts of impurities to provide the desired product. If the residence time is too long, then the column may remove desirable constituents and result in an unsuitable product. It is believed that this is particularly true for the carbon column. If the residence time on the charcoal column is too long, the amount of fatty acid component, which is indicated by the iodine value, may be adversely effected, resulting in an unsuitable product. The danger of removing desirable constituents from the treated solvent is believed to be less significant during contact with the ion exchange resin.
Residence time is a function of the amount or volume of resin or charcoal in the column and rate at which the oil is passed through the column, which may be indicated by column volumes per hour. Thus, according to the invention, if one increases the amount of, for example, charcoal in the column and hence the ratio of charcoal to polyethoxylated castor oil, then one should increase the rate at which the castor oil is run through the column accordingly, so that the actual residence time remains within acceptable parameters. With the preferred charcoal, approximately 8 Kg is used, making the column volume approximately 16 liters. Thus, at the preferred rate of 0.16 to 0.22 cv/hr, the residence time for the polyethoxylated castor oil on the column is about 2.6 to 4.8 liters per hour. Likewise, with the preferred resin, approximately 19 lbs. (8.6 Kg) yields a column volume of about 11 liters, such that the residence time of the polyethoxylated castor oil on the resin column is about 1.3 to 3.3 liters per hour at the preferred rate of 0.12 to 0.30 cv/hr.
The advantages of this invention are attained by producing this ultrapure polyethoxylated castor oil as a solvent or solubilizing agent for solubilizing pharmaceutical agents, thereby producing stabilized pharmaceutical compositions. The clarity is enhanced and the levels of deleterious impurities are lowered sufficiently to prevent degradation of pharmaceutical agents. The resulting pharmaceutical compositions can exhibit a high level of potency for prolonged periods of time.
The preferred solvent to be purified according to the invention is a polyethoxylated castor oil. Still more preferably the solvent is a polyoxyl-35 castor oil. Polyethoxylated castor oils may be prepared according to methods known in the art, or obtained commercially. As noted, the polyoxyl-35 castor oil to which the invention is particularly suited is commercially available under the tradename Cremophor EL. Other polyethoxylated castor oils, such as Cremophor RH60, can be purified in a like manner.
In accordance with the process of the invention, the solvent is first dissolved to adjust viscosity. Preferably the solvent is dissolved in an alcohol, such as ethanol. In the preferred process, one liter of dehydrated ethanol is added for every kilogram of solvent to be purified and mixed to form a solution. The solvent-alcohol solution is then first contacted with an activated carbon column. Activated carbon is a porous network of carbon and is generally neutral in charge. Once thermally activated the carbon material is hygroscopic and absorbs water. The activated carbon removes impurities from the solvent that are believed to be unsaturated aliphatic and aromatic compounds. Measurement of the iodine value before and after treatment with activated carbon results in a drop in iodine value and is generally known by those skilled in the art as an indication that unsaturated compounds have been removed. The activated carbon is believed to function as an adsorbent with respect to these colored impurities. Suitable carbon columns would be apparent to those of ordinary skill in the art in view of the present disclosure and are commercially available. Preferred charcoal for use in the invention includes Darco GTS 12xc3x974 and Norit GAC 1240 plus, commercially available from American Norit.
In carrying out the invention, the polyethoxylated castor oil solvent is contacted with the activated carbon column at a rate of from about 0.16 to 0.22 column volumes per hour (cv/hr), and still more preferably at a rate of 0.20 cv/hr. The preferred ratio of activated carbon to solvent is 0.2 Kg of activated carbon per Kg of polyethoxylated castor oil. Thus, in the preferred embodiment, employing a column volume of approximately 16 liters (8 kg of activated carbon), this yields from about 2.6 to about 4.8 liters per hour. Thus, the residence time for 1 liter is about 3.3 to 6.2 hours. As noted, if the amount of activated carbon is increased, then the flow rate should be increased so that total time spent on the column produces the desired result. Suitable amounts and flow rates to obtain the desired product, in particular the iodine value, can be readily empirically determined by one of ordinary skill in the art in view of the present invention.
The initial carbon treatment is followed by contacting the solvent with an ion exchange resin. In carrying out the preferred embodiment the eluent is pumped from the activated carbon column into a stainless steel holding tank prior to introduction to the ion exchange column. Preferably the solution is eluted through an ion exchange column at a rate of 0.12 to 0.30 cv/hour. The preferred ratios of the weight of the resin used to the polyethoxylated castor oil are between 0.21 to 0.22 Kg of resin per Kg of polyethoxylated castor oil. Suitable ion exchange resins for use in the process of the invention are commercially available from Amberlite and Dow Chemical and will be apparent to those of ordinary skill in the art in view of the present disclosure.
A preferred ion exchange resin for use in the invention is a mixed bed ion exchange resin, such as Amberlite MB 150. Preferably, the mixed bed ion exchange comprises an OHxe2x88x92 type ion exchange resin and a H+ type ion exchange resin. The OHxe2x88x92 type ion exchange resin exchanges OHxe2x88x92 for carboxylate anions and other anions present in the solvent. Likewise, the H+ type ion exchange resin exchanges H+ for potassium and other cations present. The removal of the carboxylate anions is especially preferred since it is believed that the presence of carboxylate anions in the solvent reduces stability and shelf-life of certain pharmaceutical agents, such as paclitaxel. Advantageously, the use of inventive process does not affect solvent pH. Thus, in the preferred embodiment, using a column volume of about 11 liters of resin (8.6 Kg), this yields about 1.3 to 3.3 liters per hour of clean solvent having no change in pH before and after treatment. Thus, the preferred residence time per liter is approximately 3.3 to 8.5 hours.
Once the processing through the resin column is complete, the solution is then subjected to rotary evaporation to eliminate residual water and alcohol. Other means suitable for removing residual water and alcohol, such as climbing film evaporators and the like, will also be apparent to those of ordinary skill in the art in view of the instant disclosure.
The resulting purified polyethoxylated castor oil in one embodiment, such as for polyoxyl 35 castor oil, will have a specific gravity of between 1.05 and 1.06 g/ml, a viscosity between 650 and 850 cps at 25xc2x0 C., an acid value (NF) of not more than 2.0, an hydroxyl value (NF) between 65 and 80, an iodine value (NF) between 25 and 35, a potassium content less than or equal to 15 ppm, a saponification value between 60 and 75 and a water content less than or equal to 0.5%.
The resulting purified solvent in another embodiment, such as for polysorbate 80, will have a specific gravity of between 1.06 and 1.09 g/ml, a viscosity between 300 and 500 cps, an acid value (NF) of not more than 2.2, a hydroxyl value (NF) between 65 and 80, a saponification value between 45 and 55 and a water content less than or equal to 3.0%.
The resulting purified polyethoxylated castor oil in another embodiment, such as for Cremophor RH60, will have a specific gravity of about 1.1 g/ml, a viscosity of about 211 cps at 60xc2x0 C., an acid value (NF) of less than about 0.2, an iodine value (NF) less than 2, a potassium content about 7 ppm, a saponification value of about 44 and a water content about 0.4%.
While not bound by theory, it has been found that residence times above and below the specific ranges recited for the respective charcoal and resin ratios produce lower quality polyethoxylated castor oil products having inferior value as solvents in the preparation of injectable compositions containing pharmaceutical agents. The inventive process provides a polyethoxylated castor oil that can be defined by specific values for various impurities. These purified solvents when combined with pharmaceutical agents produce the stability necessary for longer shelf-life and minimal degradation of the pharmaceutical agent.
The purified solvent prepared by the process of the present invention has, among others, reduced overall content of potassium, anion and cation impurities, acid values and water giving a pure polyethoxylated castor oil. The following non-limiting examples and the associated tables are intended to demonstrate the preferred embodiments of the invention. One skilled in the art will recognize that numerous embodiments of the invention can be practiced to achieve the purified solvent and the stabilizing effect according to the invention.